Feature Articles

Understanding of Epigenetics Deepens

As epigenetics is unveiling new layers of organization and regulation, it is becoming increasingly clear how little we knew about fundamental processes shaping biological systems.

Many transformative changes from virtually every biomedical discipline owe their existence to epigenetics. The development of new technologies and the refinement of the existing ones are marking an era when, in addition to introducing new concepts, we are also revisiting, and often reshaping, many of the existing ones.

Over 1,300 genome-wide association studies have been published since 2005. “One of the big challenges with GWAS is that there is always the concept of missing heritability,” says Peter C. Scacheri, Ph.D., associate professor of genetics and genome sciences at Case Western Reserve University.

Missing heritability refers to the fact that, for most common diseases, even after all known genetic risk factors are taken into consideration, collectively they do not explain all the heritability. For example, even though at least 42 different genes were implicated in the risk to develop type 2 diabetes mellitus, collectively they only explain approximately 20% of the heritability.

“Understanding missing heritability has been a major challenge in the field,” notes Dr. Scacheri. Some of the current views are that additional genetic variants, not yet discovered, may exist, or that epigenetic changes may hold the explanation. “It is also quite possible that the way that we have been going about GWASs to identify regions that confer genetic risk has not been done as well as it could be,” adds Dr. Scacheri.

Of the several hundred SNPs that were uncovered and linked to complex diseases, over 90% are located in noncoding regions of the genome, and many map within enhancer elements. By focusing on six autoimmune conditions, Dr. Scacheri and colleagues revealed that several SNPs in a given cell type map to multiple enhancer elements, cooperatively influencing gene expression in a model that they named the “multiple enhancer variant hypothesis.”

“We showed that many genetic loci linked to various common diseases not only localize within enhancer elements in a given cell type, but also that these combinations of genetic variants are probably contributing to the effects of gene expression and confer the risk for human disease,” asserts Dr. Scacheri.

This finding provides a new model to explain the ability of noncoding genetic variants to shape gene expression. “The way investigators should be looking for loci that confer risk to a given disease is by starting with the epigenetic marks and the chromatin maps, and using these as a basis for GWASs,” says Dr. Scacheri. Many common diseases have genetic and epigenetic components, and it is still unclear how much of the epigenetics can explain common diseases, but an intricate and multilayered interplay between genetic and epigenetic elements has increasingly been unveiled with many approaches.

Technological advances allowed investigators to study the biology of epigenetic modifications in ways that have not been available in the recent past. “But one of the challenges is that much of what has been done is still in cell lines. As the next step, we should map out epigenetic profiles in primary cells and tissues derived from the human body,” observes Dr. Scacheri.

This endeavor promises even more challenges, as every tissue has a number of distinct cell types, and epigenetic profiles are known to vary not only across cell types, but also among cells of the same type. “We think that trying to sort out the epigenetic landscape in all those specific cell types is possible, but right now it seems a little bit daunting,” concludes Dr. Scacheri.

Markers of Disease Progression

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Researchers at the Sanford-Burnham Medical Research Institute are developing genome-level epigenetic molecular markers for the early detection of malignant melanoma. Their technique involves integrating the CpG patterns obtained after pharmacologic demethylation with data from RNA-Seq experiments.

“The current challenge in dermatology is differentiating benign melanocytic nevi from primary or dysplastic melanoma, which represent the early stages of malignant differentiation,” says Ranjan J. Perera, Ph.D., associate professor and scientific director, analytical genomics and bioinformatics, at Sanford-Burnham Medical Research Institute at Lake Nona. Significant efforts in Dr. Perera’s lab are focusing on the development of markers for the early detection of malignant melanoma.

The incidence of melanoma has been steadily rising in the United States for several decades, and if diagnosed early, melanoma is curable in virtually all patients, but early diagnosis is challenging. Several million biopsies are performed annually in the United States for suspicious melanoma, and they are examined by immunohistochemistry, but variables related to the technique, the microscope, and the staining procedure affect the results.

“We are trying to add more specificity and sensitivity to the existing biomarkers,” notes Dr. Perera. He and his colleagues are focusing on developing genome-level epigenetic molecular markers that can diagnose melanoma at the earliest stages. By using next-generation sequencing, Dr. Perera and colleagues examined the genome-wide distribution of methylated CpG islands from coding and noncoding RNA genes in melanoma-derived cell lines, melanoma samples, melanocytic nevi, and normal melanocytes.

This strategy unveiled specific CpG island methylation signatures that are characteristic for melanocytes and for early and late melanoma. A progressive hypomethylation of large CpG island stretches was visualized in the early stages, which corresponds to the progression to early melanoma, while a subsequent stage, the development of late-stage melanoma, was accompanied by extensive hypermethylation. By integrating the profiles obtained after pharmacological demethylation with data from RNA-Seq experiments, Dr. Perera and colleagues described specific signatures encompassing a co-expression network of differentially expressed genes at specific stages during cancer progression.

This analysis, which mapped over 19,000 CpG sequences, illustrates the dynamic CpG methylation pattern that marks melanoma development and progression, and points toward the potential to reclassify melanomas based on their gene expression and epigenetic signatures, and to develop biomarkers. “We would actually be able to detect and obtain this information by noninvasive diagnosis, such as in serum, blood, or urine.”

Previously, Dr. Perera and colleagues were the first ones to unveil the very active role that microRNA-211 plays in regulating large numbers of genes in melanoma. Work completed since then by several groups that used next-generation sequencing revealed that microRNA-211 is the most differentially regulated microRNA in melanoma and can be used as a diagnostic marker. “The metastasis of melanoma is very fast, and the current challenge, which is finding a marker to noninvasively discriminate malignant from benign lesions in very early stages, could be lifesaving,” concludes Dr. Perera.

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